US3121664A - Stable, hermetically sealed isotonic parenteral vehicles containing buffered warfarin sodium - Google Patents
Stable, hermetically sealed isotonic parenteral vehicles containing buffered warfarin sodium Download PDFInfo
- Publication number
- US3121664A US3121664A US101689A US10168961A US3121664A US 3121664 A US3121664 A US 3121664A US 101689 A US101689 A US 101689A US 10168961 A US10168961 A US 10168961A US 3121664 A US3121664 A US 3121664A
- Authority
- US
- United States
- Prior art keywords
- sodium
- warfarin
- solution
- stable
- hermetically sealed
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- the principal objects of this invention are to provide stable solutions of Warf-arin sodium particularly suitable for iniection; and the preparation thereof.
- Warfarin 3-macetonylbenzyl-Mhydroxycomarin
- Warfarin has achieved widespread medical use for the purpose of controlling thrombotic episodes in the treatment of coronary thrombosis, myocardial infarction and analogous diseases characterized by formation of blood-clots in large blood-vessels.
- warfarin as a therapeutic agent has, in many instances, been life-saving.
- the preferred route of its administration has been via oral tablets.
- This route of administration provides the simplest means of inducing hypoprothrornbinemia. Since patients suilering from those diseases in which it is desirable to produce hypoprothrombinemia are frequently incapable of taking oral medication, either due to gastric intolerance of the drug or to being in a comatose condition as a consequence of the disease, it is frequently necessary to administer the drug by the parenteral route.
- the drug which is usually administered in the form of its sodium salt (warfiarin sodium, U.S.P.), can be administered in sterile aqueous solution by the parenteral route.
- Warfarin sodium usually consist of sterile warfarin sodium powder admixed with sodium chloride, achieved by dehydration from the frozen state, ready for redissolution in sterile distilled water.
- the solution of sodium warfarin prepared from this material, using sterile distilled water, will remain clear for from 2 to 24 hours. At some time during this period such a solution will start to deposit the free enolic compound (3-a-acertonyl-benzyl-4-hydroxycoumarin).
- warfarin sodium is administered in an initial dose of 40 to 60 rugs, in order to produce a rapid hypoprothrombinemia. After the desired level of hypoprothrombinemia is reached, this is then ice maintained by administration of small quantities of warfarin sodium: 5 to 10 mgs.
- Warfarin has the structure:
- enols are generally considerably weaker than carboxylic acids by one or two orders of magnitude in their acidity dissociation constant.
- Warfarin is an acid with a dissociation constant of the same order of magnitude as the usual carboxylic acids.
- the buffer is capable of preventing the alkalinity of the solution from exceeding some predetermined value, e.g. pH 8 to 8.5, and thus minimize the effect of alkali in increasing the alkaline color value of sodium warfarin in the presence of excess alkali.
- Such butler systems may be those which are customarily used for the maintenance of such pH values, e.g., disodium phosphate; sodium bicarbonate; sodium maleate; ammonium chloride-ammonia; ethylene diamine mono hydrochloride and ethanolamine-ethanolamine hydrochloride. These are to be considered as representative 35 examples and our invention is not limited to the use of the specific butters mentioned.
- a solution of sodium warfarin containing 25 mg. of warfarin per ml. was prepared.
- the solution was sterilized by filtration through a Selas candle of such porosity as to remove microbiological contaminants. Any other type of sterile filtration process can likewise serve adequately for this purpose.
- Aliquots of this solution were then delivered by sterile technique to vials intended for the preparation of pharmaceutical injections, and the thus filled vials were placed in a chamber at F. When the contents of the vials were solidly frozen, they were placed in a chamber which was evacuated to a pressure of below 0.1 mm., while maintaining the solid frozen state of the vial contents.
- the buffer after preparation, was delivered to a container in appropriate volume, and hermetically sealed.
- the sealed containers .and contents were sterilized by heating in an autoclave at lbs. steam pressure for 30 minutes.
- any other method of sterilization will be adequate for this purpose.
- Example 1 A buffer solution was prepared by dissolving one gram of Na HPO and 045 gram of sodium chloride in 100 ml. of water. One cc. of the thus prepared solution was added to the vial for each mg. of sodium warfarin in it, thus producing a solution containing 25 mg. of sodium warfarin, isotonic with body fluids, and buffered at a pH of 8 to 8.5. Such a solution was maintained for days without any appearance of precipitate or discoloration. The sodium warfarin content during this period of time, analyzed at 3 day intervals, was unchanged from the initial assay.
- Example 2 A buffer solution was prepared by dissolving one gram of sodium bicarbonate and 0.25 gm. of sodium chloride in 100 ml. of water. This solution was used in place of the di-sodium phosphate buffer of Example 1 in the same way for the preparation of a solution of sodium warfarin. The resulting solution had the same characteristics, property and stability as the solution produced in Example 1.
- Example 3 A buffer solution was prepared by dissolving one gram of di-sodium maleate (Na C l-I O and 0.44 gm. of sodium chloride in 100 ml. of water. This solution was substituted for the di-sodium phosphate buffer of Example 1, in the preparation of the solution of sodium warfarin. The result achieved in Example 1 was duplicated by this preparation.
- Example 4 0.40 gm. of ammonium chloride and 0.13 gm. of ammonia (NH were dissolved in 100 ml. of Water. This solution was substituted fQI i116 di-sodium phosphate buffer of Example 1 for the preparation of the solution of sodium warfarin. The analysis, color, and stability of this solution was identical with that prepared in Example 1.
- Example 5 The buffer solution of Example 1 was replaced by a buffer solution prepared from 1 gram of ethylene diamine mono hydrochloride (NH CH CH NH HCl) per mls. of solution, to yield the same result as that achieved by Example 1.
- Example 6 The bufifer solution of Example 1 was replaced by a buffer solution made up by dissolving 1.4 gms. of ethanol amino hydrochloride and 0.1 gm. of ethanol amine in 100 ml. of water.
- the solution of sodium warfarin produced by the use of this as the solvent had the same properties and analysis at the beginning and after at least 30 days of storage as the solution produced in Example 1.
- a stable, hermetically sealed isotonic parenteral vehicle containing warfarin sodium in a buffer solution wherein the buffer is a member selected from the group consisting of:
- Method of preparing a stable, hermetically sealed isontoic parenteral vehicle containing warfarin sodium which consists in adding to sterile lyophylized warfarin sodium, an isotonic solution of sodium chloride and a butler, wherein the buffer is a member selected from the group consisting of:
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
United States Patent 3,121,664 STABLE, HERME'EEQALLY dEALEl) lE'Q'iLNiC PAREFJTERAL VEHlClllEd CQJTAENENG BUR FERED WARFARHN SGEEUM Clarence F. Hislrey, Great Neclr, and Nathan Weiner, Rego Park, N.Y., assignors to Ends Laboratories inc, Richmond Hill, N.Y., a corporation of New York No Brewing. Filed Apr. 10, 1951, Ser. No. 101,639 8 Qlainas. (til. rs7 ss T his invention relates to warfarin. More particularly, it is directed to stable solutions of warfarin sodium; and the preparation thereof.
The principal objects of this invention, accordingly, are to provide stable solutions of Warf-arin sodium particularly suitable for iniection; and the preparation thereof.
The hypoprothrombinemic property of warfarin, 3-macetonylbenzyl-Mhydroxycomarin, is well-known from the smiles of Karl Link. Warfarin has achieved widespread medical use for the purpose of controlling thrombotic episodes in the treatment of coronary thrombosis, myocardial infarction and analogous diseases characterized by formation of blood-clots in large blood-vessels.
The introduction of warfarin as a therapeutic agent has, in many instances, been life-saving. The preferred route of its administration has been via oral tablets. This route of administration provides the simplest means of inducing hypoprothrornbinemia. Since patients suilering from those diseases in which it is desirable to produce hypoprothrombinemia are frequently incapable of taking oral medication, either due to gastric intolerance of the drug or to being in a comatose condition as a consequence of the disease, it is frequently necessary to administer the drug by the parenteral route. F or this purpose the drug, which is usually administered in the form of its sodium salt (warfiarin sodium, U.S.P.), can be administered in sterile aqueous solution by the parenteral route.
Unfortunately, aqueous solutions of sodium warfarin are unstable for any lengthy period of time.
Currently available injectable forms of Warfarin sodium usually consist of sterile warfarin sodium powder admixed with sodium chloride, achieved by dehydration from the frozen state, ready for redissolution in sterile distilled water. The solution of sodium warfarin prepared from this material, using sterile distilled water, will remain clear for from 2 to 24 hours. At some time during this period such a solution will start to deposit the free enolic compound (3-a-acertonyl-benzyl-4-hydroxycoumarin).
We found that this arises as a consequence of the absorption of carbon dioxide from the air. This can be prevented for varying longer periods of time by increasing the alkalinity of the sodium Warfarin with addition of small quantities of sodium hydroxide or sodium carbonate in the course of the preparation of the sterile dried sodium warfarin. However, when this is done there is produced a product which no longer corresponds to the standards of the US. Pharmacopoeia for warfarin sodium for injection, in that the material is altered so that the value, color in alkaline solution, exceeds the standard limit of 0:1 given in that compendium.
It is frequently desirable to have a solution which will be stable for longer than the above-mentioned periods of time, and of the proper standards of purity, since the use of warfarin sodium in the comatose patient may be prolonged.
In the usual conditions of use, warfarin sodium is administered in an initial dose of 40 to 60 rugs, in order to produce a rapid hypoprothrombinemia. After the desired level of hypoprothrombinemia is reached, this is then ice maintained by administration of small quantities of warfarin sodium: 5 to 10 mgs.
It is not practical to prepare solutions containing such small quantities for each particular patient, since the maintenance dose of warfarin sodium must be carefully titrated .to the patients hypoprotln ombinemic response. it is thus obvious that it is extremely desirable that there be available a stable aqueous solution of warfarin sodium, i.e., tone which will not exceed the standard for alkaline color value nor precipitate free warfarin on standing for some relatively prolonged period: e.g., 30 days.
Having discovered the reason for the increase in alkaline color value as a consequence of excess alkali and the cause of the precipitation as being due to the interaw'on of sodium warfarin with an acidifying atmosphere, we investigated the precise conditions under which we might expect warfarin sodium to be stable in solution and unaltered in alkaline color value.
The conditions for achieving solutions of warfiarin sodium with the above properties are not readily apparent. Warfarin has the structure:
The acidity of this compound, as has been pointed out by Link, is due to the enolic structure associated with the 4-hydroxycoumarin function. Enols are only weakly acidic, and generally have been found to be much less acidic than carboxylic acids. However, in order to determine the proper conditions. for achieving a stable solution of wariarin sodium, we decided to determine the pK of warfiarin, or, conversely, the pK of sodium warfarin. This was done by a speotrophotometric procedure, in which the change in spectrum of the enolic form, as stabilized by the presence of acid, was plotted against the pH of the solution. From the data thus obtained, spectrophotometrically, the pK, could be calculated.
Surprisingly, We found that the pK, of warfarin was 5.05 10.1, or that the acid dissociation constant is 1X10? This is an unexpected and surprising value.
As stated above, enols are generally considerably weaker than carboxylic acids by one or two orders of magnitude in their acidity dissociation constant.
We discovered that the dissociation constant of warfarin is nearly the same as that of the usual organic carboxylic acid; thus the acid dissociation constant of acetic acid is l.8 10- and of propionic acid is 1.4 l0 It can readily be seen that Warfarin is an acid with a dissociation constant of the same order of magnitude as the usual carboxylic acids. Thus, We unexpectedly found that it is possible to buffer solutions of sodium Warfarin with butter systems that will maintain the solution at the point of the pK of sodium Warfarin, so as to eliminate the eliect of carbon dioxide absorption and the consequent precipitation. Likewise, the buffer is capable of preventing the alkalinity of the solution from exceeding some predetermined value, e.g. pH 8 to 8.5, and thus minimize the effect of alkali in increasing the alkaline color value of sodium warfarin in the presence of excess alkali.
Such butler systems may be those which are customarily used for the maintenance of such pH values, e.g., disodium phosphate; sodium bicarbonate; sodium maleate; ammonium chloride-ammonia; ethylene diamine mono hydrochloride and ethanolamine-ethanolamine hydrochloride. These are to be considered as representative 35 examples and our invention is not limited to the use of the specific butters mentioned.
It will be recognized by those familiar with the art that a large variety of partially neutralized acids and bases, in proper proportion, can be used for maintaining a buffer pH at any value and particularly at the value herein specified.
The examples which follow illustrate several of the methods by which our invention may be practiced, but are not intended to limit the means for accomplishing the objects of this invention.
A solution of sodium warfarin containing 25 mg. of warfarin per ml. was prepared. The solution was sterilized by filtration through a Selas candle of such porosity as to remove microbiological contaminants. Any other type of sterile filtration process can likewise serve adequately for this purpose. Aliquots of this solution were then delivered by sterile technique to vials intended for the preparation of pharmaceutical injections, and the thus filled vials were placed in a chamber at F. When the contents of the vials were solidly frozen, they were placed in a chamber which was evacuated to a pressure of below 0.1 mm., while maintaining the solid frozen state of the vial contents. The ice was then permitted to sublime from the vials to a condenser maintained at a temperature below that of the vials until all of the original water had been removed. This left a residue of dehydrated sodium warfarin in the same form, shape and size as the original, frozen-solid solution. These vials were then sealed by a sterile technique with rubber diaphragm caps, held in place by aluminum or plastic seals. These vials of dried sodium warfarin serve as the source of sodium Warfarin in the examples hereafter described.
The following examples describe the preparation of a variety of buffers. In each example the buffer, after preparation, was delivered to a container in appropriate volume, and hermetically sealed. The sealed containers .and contents were sterilized by heating in an autoclave at lbs. steam pressure for 30 minutes. However, any other method of sterilization will be adequate for this purpose.
Example 1 A buffer solution was prepared by dissolving one gram of Na HPO and 045 gram of sodium chloride in 100 ml. of water. One cc. of the thus prepared solution was added to the vial for each mg. of sodium warfarin in it, thus producing a solution containing 25 mg. of sodium warfarin, isotonic with body fluids, and buffered at a pH of 8 to 8.5. Such a solution was maintained for days without any appearance of precipitate or discoloration. The sodium warfarin content during this period of time, analyzed at 3 day intervals, was unchanged from the initial assay.
Example 2 A buffer solution was prepared by dissolving one gram of sodium bicarbonate and 0.25 gm. of sodium chloride in 100 ml. of water. This solution was used in place of the di-sodium phosphate buffer of Example 1 in the same way for the preparation of a solution of sodium warfarin. The resulting solution had the same characteristics, property and stability as the solution produced in Example 1.
Example 3 A buffer solution was prepared by dissolving one gram of di-sodium maleate (Na C l-I O and 0.44 gm. of sodium chloride in 100 ml. of water. This solution was substituted for the di-sodium phosphate buffer of Example 1, in the preparation of the solution of sodium warfarin. The result achieved in Example 1 was duplicated by this preparation.
Example 4 0.40 gm. of ammonium chloride and 0.13 gm. of ammonia (NH were dissolved in 100 ml. of Water. This solution was substituted fQI i116 di-sodium phosphate buffer of Example 1 for the preparation of the solution of sodium warfarin. The analysis, color, and stability of this solution was identical with that prepared in Example 1.
Example 5 The buffer solution of Example 1 was replaced by a buffer solution prepared from 1 gram of ethylene diamine mono hydrochloride (NH CH CH NH HCl) per mls. of solution, to yield the same result as that achieved by Example 1.
xample 6 The bufifer solution of Example 1 was replaced by a buffer solution made up by dissolving 1.4 gms. of ethanol amino hydrochloride and 0.1 gm. of ethanol amine in 100 ml. of water. The solution of sodium warfarin produced by the use of this as the solvent had the same properties and analysis at the beginning and after at least 30 days of storage as the solution produced in Example 1.
It will be understood that the foregoing description of the invention and the examples set forth are merely illustrative of the principles thereof. Accordingly, the appended claims are to be construed as defining the invention within the spirit and scope thereof.
We claim:
1. A stable, hermetically sealed isotonic parenteral vehicle containing warfarin sodium in a buffer solution, wherein the buffer is a member selected from the group consisting of:
(A) disodium hydrogen phosphate,
(B) sodium bicarbonate,
(C) disodium maleate,
(D) ammonium chloride and ammonia,
(E) ethylene diamine monohydrochloride,
(F) ethanolamine hydrochloride and ethanolamine,
and sodium chloride at a pH of 8.0 to 8.5.
2. A stable, hermetically sealed isotonic parenteral vehicle in accordance with claim 1 wherein the buffer is (A) as defined in claim 1.
3. A stable, hermetically sealed isotonic parenteral vehicle in accordance with claim 1 wherein the buffer is (B) as defined in claim 1.
4. A stable, hermetically sealed isotonic parenteral vehicle in accordance with claim 1 wherein the buffer is (C) as defined in claim 1.
5. A stable, hermetically sealed isotonic perenteral vehicle in accordance with claim 1 wherein the butter is (D) as defined in claim 1.
6. A stable, hermetically sealed isotonic parenteral vehicle in accordance with claim 1 wherein the butter is (E) as defined in claim 1.
7. A stable, hermetically sealed isotonic parenteral vehicle in accordance with claim 1 wherein the bufier is (F) as defined in claim 1.
8. Method of preparing a stable, hermetically sealed isontoic parenteral vehicle containing warfarin sodium which consists in adding to sterile lyophylized warfarin sodium, an isotonic solution of sodium chloride and a butler, wherein the buffer is a member selected from the group consisting of:
(A) disodium hydrogen phosphate,
(B) sodium bicarbonate,
(C) disodium maleate,
(D) ammonium chloride and ammonia,
(E) ethylene diarnine monohydrochloride,
(F) ethanolamine hydrochloride and ethanolamine,
thereby to provide a pH of 8.0 to 8.5.
References Cited in the file of this patent UNITED STATES PATENTS 2,601,204 Campbell et al. June 17, 1952 2,783,177 Link Feb. 26, 1957 2,999,049 Link Sept. 5, 1961
Claims (1)
1. A STABLE, HERMETICALLY SEALED ISOTONIC PARENTERAL VEHICLE CONTAINING WARFARIN SODIUM IN A BUFFER SOLUTION, WHEREIN THE BUFFER IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF: (A) DISODIUM HYDROGEN PHOSPHATE, (B) SODIUM BICARBONATE, (C) DISODIUM MALEATE, (D) AMMONIUM CHLORIDE AND AMMONIA, (E) ETHYULENE DIAMINE MONOHYDROCHLORIDE, (F) ETHANOLAMINE HYDROCHLORIDE AND ETHANOLAMINE, AND SODIUM CHLORIDE AT A PH OF 8.0 TO 8.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US101689A US3121664A (en) | 1961-04-10 | 1961-04-10 | Stable, hermetically sealed isotonic parenteral vehicles containing buffered warfarin sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US101689A US3121664A (en) | 1961-04-10 | 1961-04-10 | Stable, hermetically sealed isotonic parenteral vehicles containing buffered warfarin sodium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3121664A true US3121664A (en) | 1964-02-18 |
Family
ID=22285902
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US101689A Expired - Lifetime US3121664A (en) | 1961-04-10 | 1961-04-10 | Stable, hermetically sealed isotonic parenteral vehicles containing buffered warfarin sodium |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3121664A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060293382A1 (en) * | 2005-06-15 | 2006-12-28 | Weldele Meagan E | Stable warfarin sodium liquid formulation and method of making same |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2601204A (en) * | 1947-11-15 | 1952-06-17 | Wisconsin Alumni Res Found | Process of lowering blood prothrombin level and lengthening clotting time with methylenebis-hydroxy coumarin |
| US2783177A (en) * | 1952-03-17 | 1957-02-26 | Wisconsin Alumni Res Found | Warfarin sodium rodenticidal composition |
| US2999049A (en) * | 1959-03-27 | 1961-09-05 | Wisconsin Alumni Res Found | Warfarin sodium and heparin sodium composition |
-
1961
- 1961-04-10 US US101689A patent/US3121664A/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2601204A (en) * | 1947-11-15 | 1952-06-17 | Wisconsin Alumni Res Found | Process of lowering blood prothrombin level and lengthening clotting time with methylenebis-hydroxy coumarin |
| US2783177A (en) * | 1952-03-17 | 1957-02-26 | Wisconsin Alumni Res Found | Warfarin sodium rodenticidal composition |
| US2999049A (en) * | 1959-03-27 | 1961-09-05 | Wisconsin Alumni Res Found | Warfarin sodium and heparin sodium composition |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060293382A1 (en) * | 2005-06-15 | 2006-12-28 | Weldele Meagan E | Stable warfarin sodium liquid formulation and method of making same |
| US7259185B2 (en) * | 2005-06-15 | 2007-08-21 | Morton Grove Pharmaceuticals, Inc. | Stable warfarin sodium liquid formulation and method of making same |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4396608A (en) | Intravenously injectable immune serum globulin | |
| US3062717A (en) | Intramuscular calcium tetracycline acetic or lactic acid carboxamide vehicle preparation | |
| US4499073A (en) | Intravenously injectable immune serum globulin | |
| ES2298295T3 (en) | LIOFILIZED PREPARATION OF PANTOPRAZOL AND INJECTION OF PANTOPRAZOL. | |
| US4647454A (en) | Stable interferon β composition and a method of stabilizing interferon β | |
| KR870000918A (en) | Pharmaceutical dosage unit | |
| IE58639B1 (en) | 9-substituted guanine monohydrates | |
| CA1056729A (en) | Injectable amoxycillin composition | |
| EP0253662B1 (en) | Pharmaceutical compositions | |
| US4486423A (en) | Stable fentanyl composition | |
| US4670258A (en) | Storable prepackaged aqueous solutions of vancomycin | |
| MX2007004490A (en) | Compositions containing piperacillin, tazobactam and a aminocarboxilic acid in a sodium lactate diluent. | |
| US4616083A (en) | Stable antibacterial lyophilizates | |
| JP3439855B2 (en) | Pharmaceutical products and their manufacturing method | |
| CN105919931B (en) | A kind of fasudil hydrochloride injection of stabilization and preparation method thereof | |
| US3121664A (en) | Stable, hermetically sealed isotonic parenteral vehicles containing buffered warfarin sodium | |
| KR900003491B1 (en) | Ifosfamide lyophilisate and preparation method thereof | |
| WO2009047634A2 (en) | Aqueous formulations of acetaminophen for injection | |
| US2249903A (en) | Stable aqueous solution of ascorbic acid | |
| JP3636372B2 (en) | Mesna injection solution, process for producing the same, and medicament for avoiding side effects of oxyazaphospholine comprising the same | |
| US2644782A (en) | Aureomycin for injection | |
| SK13522003A3 (en) | Injectable pamidronate disodium | |
| GB9302455D0 (en) | Process for preparing a pharmaceutical preparation having neuromuscular blocking activity | |
| JPH04211611A (en) | Immunity stimulating drug administrable through non-intestinal route and stable to storage and method of its preparation | |
| JPH01146826A (en) | Lyophilized pharmaceutical of platinum compound |